v1.0 researched and written by Luisa Arueira, edited by Suerie Moon, last updated April 2019 
The problem of medicines shortages has received increasing attention in recent years, and affects health systems at local, national and global levels. This review identifies and characterizes the literature on medicines shortages, including the definition, causes, consequences and proposals to address shortages, concluding with research gaps.
Pharmaceutical/medicine/drug and shortage
SYNTHESIS OF THE LITERATURE
The literature on shortages is considerable,* mainly focused on the description of medicines shortages, its consequences and coping strategies. Publications on the subject are recent, with the great majority having been published after 2011; a large number of these are notes, letters to the editor, comments, opinion articles, and communications.
The majority of papers are concentrated in the United States (US) and in high-income countries. Only 6 studies were found conducted in low and middle-income countries: two from Iran ((Butler, 2013; Gholami, Kamalinia, Ahmadian Attari, & Salamzadeh, 2012), one from Zambia (Chomba et al., 2010), Kenya (Kangwana et al., 2009), Malawi (Lufesi, Andrew, & Aursnes, 2007) and Brazil (Reis & Perini, 2008).
Most articles discussed medicines shortages in general. Of those that examined a specific medicine or therapeutic class, many focused on antineoplastics and immunomodulant agents, followed by parenteral nutrition and its components, and anesthetics. It is worth noting a large number of citations related to oncology medicines for the pediatric population and injectables in general.
CONCEPTS AND DEFINITIONS
There is no single definition of a shortage. Of the identified articles that include a conceptual discussion, one was an opinion piece (Duffy, 2012) and two were empirical research (De Weerdt, Simoens, Casteels, & Huys, 2015; Reis & Perini, 2008). De Weerdt et al (2015) through a review of the scientific and gray literature and interviews, sought to define the concept of "drug shortage" in the European community. In order to do so, bibliographic searches were carried out in two databases as well as a manual search on the websites of regulatory bodies and professional organizations. The authors also investigated how long a product has to be out of stock to be considered a shortage. They concluded that there were two general definitions of shortages, one referring to when to notify regulatory agencies and another for the designation of a shortage. There is no unified definition linking these two aspects of shortages, nor to facilitate comparison between different information systems and studies.
DESCRIPTION OF THE PROBLEM
Of the publications that focused on describing shortages, half were composed of communications, editorials, and opinion articles, which in general communicated the existence of shortages, called for action to solve the problem, and/or proposed therapeutic alternatives to medicines in shortage (Alspach, 2012a, 2012b; Carter, 2011; Dal Moro, 2013; Fox & Tyler, 2013; Mayer, 2012; Mirtallo, 2011; Navarro, Norman, Pérez-Molina, & López-Vélez, 2012; Printz, 2012; Tomlin, 2016; Traynor, 2011; Wenzel, 2015). The other papers emphasized the seriousness of the problem, demonstrating that it is a growing problem in recent years, is a part of the daily life of health professionals, reports cases in healthcare settings, and their impact on patients' health (Bauters et al., 2015; Costelloe, Guinane, Nugent, Halley, & Parsons, 2015; Gundlapalli, Beekmann, Graham, & Polgreen, 2013; Hawley, Mazer-Amirshahi, Zocchi, Fox, & Pines, 2016; Hvisdas, Lordan, Pizzi, & Thoma, 2013; Kaposy, 2014; Palm & Dotson, 2015; Pauwels, Huys, Casteels, & Simoens, 2014; Quadri et al., 2015; Reed et al., 2016).
Only a few studies examined the causes of shortages. Of the three articles identified that did so, two (Lufesi et al., 2007; Woodcock & Wosinska, 2012) were empirical studies while one was an editorial that emphasized the importance of further research on causes (Blum, 2014). From the empirical studies, Lufesi et al (2007) identified as the cause of medicines shortage in Malawi the deficiency of the local distribution system. Woodcock and Wosinka (2012), when analyzing the shortage of injectables in the United States, indicated as causes problems related to the quality of medicines that led to the interruption of production. The authors pointed out that the production of injectables is more complex and expensive, and quality cannot easily be measured by the final consumer. Thus, producers underinvest in infrastructure, eventually leading to problems in manufacturing that may result in shortages. This problem is worsened by the small number of producers of injectables medicines. The authors proposed that regulatory agencies assign quality indicators to production sites to inform consumer decision-making, that financial incentives for higher quality injectable production be provided, and these measures would result in fewer problems with interruption of manufacturing and greater availability (Woodcock & Wosinska, 2012).
A number of papers focused on the consequences of shortages. Reported consequences included: substitution for less effective and more toxic therapies for patients (Becker et al., 2013; Kehl et al., 2015; Kosarek, Hart, Schultz, & DiGiovanni, 2011), higher costs (Bible, Evans, Payne, & Mostafavifar, 2014; Dorsey et al., 2009; Havrilesky, Garfield, Barnett, & Cohn, 2012; Hayes, Ward, Slabaugh, & Xu, 2014; M. McLaughlin et al., 2013; Ralls et al., 2012), worsening of biochemical parameters (Corrigan & Kirby, 2012; Davis, Javid, & Horslen, 2014; Pramyothin, Kim, Young, Wichansawakun, & Apovian, 2013), delay in clinical trials (Salazar, Bernhardt, Li, Aplenc, & Adamson, 2015), increased rates of adverse events (Hall et al., 2013; Holcombe, 2012; M. McLaughlin et al., 2013; Sheth, Verrico, Skledar, & Towers, 2005; Wuerz, Bow, & Seftel, 2013), and worse clinical outcomes due to discontinuation of therapy (Ruktanonchai et al., 2014). In contrast, eight papers found no significant differences, or even observed better clinical outcomes of patients after therapy discontinuation or dose reduction (Deroma et al., 2012; Goldblatt, Fletcher, McGill, Szer, & Wilson, 2011; Hughes, Goswami, & Morris, 2015; Storey et al., 2016; Thoma et al., 2014; Tolia, Murthy, McKinley, Bennett, & Clark, 2014). Interestingly, Liang and Mackey (2012) found that medicines in short supply were being sold online at exorbitant prices, supporting the argument that shortages may fuel underground markets in medicines.
PROPOSALS OR RECOMMENDATIONS
In terms of recommendations, publications focused on coping strategies put in place and their results, reported on expert opinions on how to manage medicines shortages, health professionals' perceptions regarding what needed to be done, and/or advocated for certain actions (Barlas, 2013; Eggertson, 2011; Sirrs, 2011; Vogel, 2012). The main coping strategies cited were: fiscal and quality incentives (e.g. letter grades on the quality of manufacturing sites) to companies in exchange for continued production and alteration of the inspection system (Schweitzer, 2013); timely information on shortages for prescribers, patients and pharmacies (Hsia et al., 2015; Mirtallo, Holcombe, Kochevar, & Guenter, 2012); guarantee of an emergency stock of critical drugs (Peter, 2006); preparation of an action plan for cases of shortages, listing priorities for care, management strategies and possible therapeutic alternatives (Beck, Smith, Gordon, & Garrett, 2015; DeCamp, Joffe, Fernandez, Faden, & Unguru, 2014; Krisl, Fortier, & Taber, 2013; Plogsted, Adams, Allen, Breen, et al., 2016; Plogsted, Adams, Allen, Cober, et al., 2016; Singleton et al., 2013; Valgus, Singer, Berry, & Rathmell, 2013); use of therapeutic alternatives, even if they are off-label (Berthe-Aucejo et al., 2014; M. L. de Lemos, Waignein, & Haan, 2016); establishing a partnership with the pharmaceutical industry (Jensen & Throckmorton, 2015); contracting pharmacists specifically to monitor stocks and handle shortages (Caulder, Mehta, Bookstaver, Sims, & Stevenson, 2015); training of health professionals (Eggertson, 2011; Jagsi et al., 2014); use of medicines beyond their expiry date in critical situations (M. de Lemos, Kletas, Man, & Walisser, 2012); use of information systems to monitor adverse effects due to shortages (M. M. McLaughlin, Skoglund, Pentoney, & Scheetz, 2014); and use of alternative infusion techniques to reduce the necessary dose (McHugh & Ibinson, 2013; Parbhoo et al., 2014).
Conceptual work is needed to better define shortages, stock-outs and when these should be notified to regulatory agencies;
Further studies on shortages in middle and low-income countries are needed.
Mapping of active pharmaceutical ingredient (API) and finished product manufacturing sources is needed, especially for off-patent and low-price medicines for which profit margins and the incentive to produce may be relatively low.
Further research is needed on the causes of medicines shortages, especially analysis that includes global determinants.
Increased analysis is needed on the range, effectiveness and consequences of coping strategies in the face of shortages.
 This synthesis of the literature is based on a longer review: Chaves LA, Chaves GC, Vianna MNS, Oliveira MA. Desabastecimento de medicamentos na literatura científica da saúde: uma revisão narrativa. Physis Rev Saúde Coletiva. in-press. http://dx.doi.org/10.1590/S0103-73312019290107 (in Portuguese).
CITED PAPERS WITH ABSTRACTS
* For the purposes of this review, we have established three categories to describe the state of the literature: thin, considerable, and rich.
- Thin: There are relatively few papers and/or there are not many recent papers and/or there are clear gaps
- Considerable: There are several papers and/or there are a handful of recent papers and/or there are some clear gaps
- Rich: There is a wealth of papers on the topic and/or papers continue to be published that address this issue area and/or there are less obvious gaps
Scope: While many of these issues can touch a variety of sectors, this review focuses on medicines. The term medicines is used to cover the category of health technologies, including drugs, biologics (including vaccines), and diagnostic devices.
Disclaimer: The research syntheses aim to provide a concise, comprehensive overview of the current state of research on a specific topic. They seek to cover the main studies in the academic and grey literature, but are not systematic reviews capturing all published studies on a topic. As with any research synthesis, they also reflect the judgments of the researchers. The length and detail vary by topic. Each synthesis will undergo open peer review, and be updated periodically based on feedback received on important missing studies and/or new research. Selected topics focus on national and international-level policies, while recognizing that other determinants of access operate at sub-national level. Work is ongoing on additional topics. We welcome suggestions on the current syntheses and/or on new topics to cover.